In this aging society, it is desired to develop a technique for rebuilding deficits and injuries on such tissues as bones and teeth. Progress in regeneration medicine arouses an interest especially toward a skeletal system biomaterial. As a revolutionary technique for repairing lost tissues, it is desired to develop artificial bone marrow and artificial dental pulp that are components of hard tissues.
Especially in the dentistry field, a medical treatment for preserving dental pulp tissues is increasingly becoming important since it is desirable to live with own teeth as long as possible. Dental pulp is centrally located in a tooth, and comprises ground substance, blood vessel, and nerve. In the case in which the tooth was affected with caries and the affection spread to a part of the dental pulp, a useful treatment that is gathering attention is a vital pulptectomy, in which only a site of infection is locally severed and rest of the dental pulp is preserved.
However, in reality, appropriately treating a severed surface of the dental pulp is technically difficult, and it is not always promising to keep the severed dental pulp in good condition. Therefore, it is desired to establish a least-invasive treatment method for more appropriately treating the dental pulp. In this situation, if a deficit on the dental pulp due to excision of an affected site can be restored to an original state and the dental pulp tissue can be preserved, this may significantly contribute to improvement in people's QOL and reduction of medical cost.
Various types of skeletal system biomaterials for repairing defects in bone tissues have been studied from a viewpoint of biodegradability of a carbonate apatite (CO3Ap). The inventors propose use of a carbonate apatite-collagen complex as a biomaterial. The carbonate apatite-collagen complex is produced from the carbonate apatite and a collagen, which are similar to a living hard tissue in terms of chemical composition and crystallinity degree (See non-patent document 1 and non-patent document 2). The carbonate apatite-collagen complex showed a good biocompatibility when inserted into abdomen or under pericranium of a rat.
However, an inner bulk of the carbonate apatite-collagen complex has no room for cells to infiltrate into. It was found that when use of a sponge-like carbonate apatite-collagen complex provides large pores, proliferation of osteoblasts and infiltration of cells into the pores were promoted (See non-patent document 3).
In order for the biomaterial to survive after regeneration of a lost tissue so that the biomaterial fully exercises its function, it is essential to provide oxygen and nutrients to cells. That is, blood vessels for giving hybrid functions to the skeletal system biomaterial is necessary for maintenance and growth of bones.
As described above, the carbonate apatite-collagen complex shows appropriate biocompatibility, and the sponge-like material of the complex includes enough room for the cells to infiltrate into. However, even if the cells were infiltrated into the sponge-like material, the cells would not be able to survive without the blood vessels that provide oxygen and nutrients. Therefore, angiogenesis inside the biomaterial is essential.
A process of angiogenesis is started with digesting blood vessel basement membrane with endothelial cells. After that, the cells move and proliferate to form a canal structure. It is reported by many researchers that the cellular reactions are rigorously controlled by a signal emitted from such factors as various growth factors and a cytokine (vessel endothelial growth factor (VEGF), fibroblast growth factor (FGF), and interleukin 8).
An osteopontin (OPN), which is an extracellular matrix protein, is a protein phosphate containing a large amount of sialic acid, and is widely distributed in bones, kidney, brain, skin, and the like. The OPN relates to bone metabolism, and intermediates an inflammation reaction and the angiogenesis. Recently, an amino-acid sequence [Ser-Val-Val-Tyr-Gly-Leu-Arg (SVVYGLR)] (SEQ ID NO: 1) relating to an angiogenic action has been found in the OPN (See patent document 1, non-patent document 4, and non-patent document 5). The SVVYGLR (SEQ ID NO: 1), which adjacents to an RGD sequence within a molecule of the osteopontin, was being exposed by thrombin cleavage, so this motif is believed to play an important role in a clinical condition. We have already succeeded in artificially composing the sequence of SVVYGLR (SEQ ID NO: 1) as a blood vessel growth factor (See non-patent document 6).